title: CYP3A time-dependent inhibition risk assessment validated with 400 reference drugs.
abstract: Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (k(inact) and K(I)) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (k(obs)) at a single concentration of test compound (10 μM). The advantages of this new assay format are highlighted by comparison with data generated using the IC₅₀ shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically defined positive/negative k(obs) bin of 0.02 min⁻¹, only 4% of registered drugs were found to be positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling.
authors.affiliation: Discovery ADME, Novartis Institutes for BioMedical Research, WSJ-350.3.12, P.O. Box, CH-4002 Basel, Switzerland. alfred.zimmerlin@novartis.com
authors.forename: Alfred
authors.initials: A
authors.lastname: Zimmerlin
authors.forename: Markus
authors.initials: M
authors.lastname: Trunzer
authors.forename: Bernard
authors.initials: B
authors.lastname: Faller
mesh_terms: D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D015203:Reproducibility of Results; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D015507:Drugs, Investigational; D004364:Pharmaceutical Preparations; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A